Application of a Novel UPLC-MS/MS Method for Analysis of Rivaroxaban Concentrations in Dried Blood Spot and Plasma Samples Collected from Patients with Venous Thrombosis
Abstract
:1. Introduction
2. Results
2.1. UPLC-MS/MS Conditions
2.2. Method Validation
2.2.1. Selectivity
2.2.2. Calibration Curve
2.2.3. LLOQ, Accuracy and Precision
2.2.4. Recovery and Matrix Effect
2.2.5. Dilution Integrity
2.2.6. Stability
2.2.7. Correlation of the Rivaroxaban Concentration in DBS and Plasma
2.2.8. Hematocrit and Blood Spot Volume
2.2.9. Clinical Samples
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. UHPLC-MS/MS and Chromatographic Conditions
4.3. Standard Solutions
4.3.1. Preparation of Calibrators and Quality Control Samples
4.4. Method Validation
4.4.1. Selectivity
4.4.2. Calibration Curves
4.4.3. LLOQ, Accuracy and Precision
4.4.4. Carry-Over Effect
4.4.5. Recovery
4.4.6. Matrix Effect
4.4.7. Dilution Integrity
4.4.8. Stability
4.4.9. Hematocrit and Blood Spot Volume
4.4.10. Correlation of the Rivaroxaban Concentration in DBS and Plasma
4.4.11. Clinical Application
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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QC Concentration | Plasma Samples | DBS Samples | |||
---|---|---|---|---|---|
Intra-Day (n = 5) | Inter-Day (n = 6) | Intra-Day (n = 5) | Inter-Day (n = 6) | ||
2 ng/mL (LLOQ) | RSD% | 14.21 | 10.43 | 3.85 | 10.89 |
RE% | −4.77 | −10.05 | −16.55 | −9.71 | |
5 ng/mL (LQC) | RSD% | 7.86 | 7.81 | 1.87 | 12.09 |
RE% | −2.68 | −1.60 | 1.16 | 5.74 | |
200 ng/mL (MQC) | RSD% | 14.54 | 7.60 | 3.26 | 3.78 |
RE% | −12.79 | −1.74 | −3.03 | 1.89 | |
500 ng/mL (HQC) | RSD% | 9.82 | 5.54 | 7.66 | 1.70 |
RE% | 0.99 | 0.91 | 3.00 | −1.26 |
Concentration of Rivaroxaban [ng/mL] | Extraction Recovery (Mean Value (RSD%)) | Concentration of Rivaroxaban [ng/mL] | IS-Normalized MF (Mean Value (RSD%)) |
---|---|---|---|
Plasma samples | n = 5 | n = 6 | |
5 | 71.73 (12.27) | 5 | 0.96 (1.53) |
200 | 60.24 (9.97) | ||
400 | 69.11 (8.04) | 500 | 1.04 (1.24) |
DBS samples | n = 5 | n = 6 | |
5 | 66.77 (10.08) | 5 | 0.93 (4.86) |
200 | 50.19 (7.15) | ||
500 | 52.17 (7.94) | 500 | 0.97 (4.67) |
DBS Samples | ||||||
---|---|---|---|---|---|---|
Stability Test | Conditions | Nominal Concentration [ng/mL] | Initial Mean Concentration ± SD [ng/mL] before Stability Test | Mean Concentration ± SD [ng/mL] after Stability Test | RSD% | RE% |
A | +4 °C (113 days) | 5 | 4.92 ± 0.06 | 5.42 ± 0.38 | 6.92 | 8.42 |
500 | 524.87 ± 21.81 | 553.90 ± 44.14 | 7.97 | 10.78 | ||
−25 °C (113 days) | 5 | 4.92 ± 0.06 | 5.29 ± 0.15 | 3.94 | 5.89 | |
500 | 524.87 ± 21.81 | 499.80 ± 27.33 | 5.47 | 0.04 | ||
−80 °C (113 days) | 5 | 4.92 ± 0.06 | 4.96 ± 0.20 | 2.80 | 0.87 | |
500 | 524.87 ± 21.81 | 493.21 ± 14.90 | 3.02 | 1.36 | ||
B | 10 °C (48 h) | 5 | 4.93 ± 0.40 | 4.93 ± 0.47 | 9.47 | 1.49 |
500 | 516.39 ± 7.90 | 557.62 ± 10.74 | 1.93 | 11.52 | ||
C | 20 °C (4 h) | 5 | 5.33 ± 1.24 | 4.90 ± 0.99 | 7.95 | 0.02 |
500 | 511.60 ± 33.65 | 542.27 ± 13.47 | 5.99 | 8.45 | ||
D | 20 °C (4 h) | 5 | 5.00 ± 0.37 | 5.37 ± 0.47 | 8.72 | 7.44 |
500 | 541.79 ± 41.70 | 547.98 ± 19.11 | 3.49 | 9.60 |
Plasma Samples | ||||||
---|---|---|---|---|---|---|
Stability Test | Conditions | Nominal Concentration [ng/mL] | Initial Mean Concentration ± SD [ng/mL] before Stability Test | Mean Concentration ± SD [ng/mL] after Stability Test | RSD% | RE% |
A | −25 °C (31 days) | 5 | 5.10 ± 1.04 | 4.54 ± 1.11 | 3.06 | 0.50 |
400 | 399.51 ± 44.93 | 429.81 ± 0.75 | 2.50 | 3.06 | ||
B | 10 °C (24 h) | 5 | 5.48 ± 1.14 | 4.74 ± 0.32 | 2.72 | 1.65 |
400 | 388.57 ± 37.54 | 392.16 ± 37.87 | 4.03 | 2.05 | ||
C | 20 °C (4 h) | 5 | 5.60 ± 0.61 | 6.23 ± 1.26 | 0.86 | 3.26 |
400 | 338.53 ± 32.09 | 360.76 ± 26.72 | 3.11 | 0.09 | ||
D | −25 °C (3 cycles) | 5 | 4.87 ± 0.77 | 4.31 ± 0.46 | 10.67 | 13.8 |
400 | 366.98 ± 18.72 | 349.82 ± 9.16 | 2.62 | 12.55 |
Hematocrit Value [%] | LQC | HQC | ||
---|---|---|---|---|
RSD% | RE% | RSD% | RE% | |
48.5 | 1.55 | 2.53 | 6.47 | 0.39 |
40.0 | 2.63 | 0.07 | 3.20 | 2.75 |
31.5 | 2.74 | 1.73 | 3.84 | 0.03 |
Sampling spot volume [µL] | ||||
15 | 6.61 | 4.27 | 2.38 | 4.30 |
20 | 10.72 | 8.61 | 0.47 | 2.00 |
25 | 7.92 | 5.05 | 1.90 | 5.64 |
Parameter Measured (n = 18) | Mean ± SD |
---|---|
Age [years] | 53.83 ± 15.61 |
Body weight [kg] | 80.94 ± 16.69 |
Height [cm] | 169.71 ± 7.94 |
BMI [kg/m2] | 27.90 ± 4.13 |
aPTT [s] | 46.20 ± 6.54 |
PT [s] | 16.54 ± 2.78 |
INR | 1.46 ± 0.25 |
DD [ng/mL] | 271 (227.25–413.25) 1 |
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Pawlak, K.; Kruszyna, Ł.; Miecznikowska, M.; Karaźniewicz-Łada, M. Application of a Novel UPLC-MS/MS Method for Analysis of Rivaroxaban Concentrations in Dried Blood Spot and Plasma Samples Collected from Patients with Venous Thrombosis. Molecules 2024, 29, 4140. https://doi.org/10.3390/molecules29174140
Pawlak K, Kruszyna Ł, Miecznikowska M, Karaźniewicz-Łada M. Application of a Novel UPLC-MS/MS Method for Analysis of Rivaroxaban Concentrations in Dried Blood Spot and Plasma Samples Collected from Patients with Venous Thrombosis. Molecules. 2024; 29(17):4140. https://doi.org/10.3390/molecules29174140
Chicago/Turabian StylePawlak, Kornel, Łukasz Kruszyna, Marta Miecznikowska, and Marta Karaźniewicz-Łada. 2024. "Application of a Novel UPLC-MS/MS Method for Analysis of Rivaroxaban Concentrations in Dried Blood Spot and Plasma Samples Collected from Patients with Venous Thrombosis" Molecules 29, no. 17: 4140. https://doi.org/10.3390/molecules29174140